Michael Gordon

Gordon Lab Webpage

Our mission will be to understand the organization, function, and development of neural circuits that process sensory information in the tiny brain of the fruit fly.

Shernaz Bamji

Bamji Lab Webpage

Synapses are the essential point of contact between neurons and their targets for the directional flow of information in the nervous system. The study of how synapses form and how they function is fundamental to our understanding of nervous system connectivity and communication. It is now believed that deficiencies in synaptic function are central to many psychiatric and neurodegenerative diseases such as schizophrenia, Alzheimer’s, Parkinson’s and Huntington’s disease. Thus, it is anticipated that a better understanding of the molecular mechanisms that control these highly specialized structures holds great promise for the development of urgently needed, novel therapies for these diseases.

The principle research objective of my laboratory is to elucidate the cellular and molecular mechanisms underlying the formation, stability, and elimination of CNS synapses. We primarily utilize cultured hippocampal neurons as a model system, and extend these studies to genetically modified mouse models when appropriate. Fundamental questions addressed in the lab include; 1) how does cell-cell contact result in the assembly of pre- and postsynaptic compartments, 2) what are the contributions of pre- and postsynaptic elements to the integrity of the synapse, 3) what are the transsynaptic signals that regulate synaptic plasticity, and 4) is synapse elimination a stereotypical process and, if so, what is the sequence of molecular events underlying synapse disassembly?

Answers to these questions will not only reveal mechanisms underlying developmental and neurodegenerative disorders, but will also provide insight into the molecular signals involved in synaptic strengthening, a process believed essential for learning and memory.

Linda Matsuuchi

Matsuuchi Lab Website

My lab is interested in understanding intracellular trafficking and cell signaling of specific membrane receptors, combining aspects of Cell Biology, Immunology , Biochemistry and Molecular Biology.
Structure and function of the antigen receptor on B lymphocytes: The B cell receptor is composed of membrane immunoglobulin M (mIgM) and a heterodimer of two associated proteins, Ig-alpha and Ig- beta. When the receptor is on the cell surface of B lymphocytes it functions to transmit intracellular signals that regulate cell growth and differentiation and it binds to antigen for the generation of the immune response. We are studying what regulates the association between the chains of the receptor and the intracellular trafficking of the receptor to the cell surface. In addition we are interested in how the B cell receptor interacts with components of the intracellular signaling machinery, in particular protein tyrosine kinases, phosphatases and other associated proteins.

Don Moerman

Moerman Lab Webpage

Our laboratory is interested in the formation and function of muscle in the free-living nematode C. elegans. Muscle sarcomere assembly is a highly orchestrated affair involving several proteins. The steps involved in initiating the correct placement of sarcomere substructures is poorly understood. Using mutants in Caenorhabditis elegans we are attempting to dissect the various steps in this process. One interpretation of the current data is that assembly of sarcomeres initiates at the plasma membrane and involves proteins within muscle and within the extracellular matrix.

Studies on muscle mutants with defects in either thick or thin filament components suggests these components do not regulate sarcomere assembly. Recent studies implicate the dense body, the nematode analog of a vertebrate Z-line, as a key component regulating sarcomere initiation, length and orientation. Mutations in the unc-52 gene affect this structure and consequently sarcomere assembly. We have shown that theunc-52 gene encodes a basement membrane proteoglycan similar to vertebrate perlecan. The UNC-52 protein is a component of the extracellular matrix (ECM) underlying all muscle and is concentrated under the transmembrane integrin complexes which anchor muscle sarcomeres. Our current studies are directed at determining how nematode perlecan and other components of the ECM interact with muscle constituents to regulate muscle sarcomere assembly. In collaboration with other laboratories we have shown in recent years that the muscle cell proteins UNC-112, UNC-97/PINCH, PAT-4/ILK and integrin are all essential for myofilament assembly.

Ivan Robert Nabi

Nabi Lab Webpage

Work in the Nabi lab focuses on cell biology and its relation to disease, in particular cancer. The expression of cellular domains, ranging from cell polarity to organelle biogenesis to membrane microdomain organization, plays an important role in regulating cell function. Domain localization is critical to the regulation of receptor activation and our work has elaborated on the functional significance of various cellular domains in receptor function in cell motility.

Specific projects include:
• The role of autocrine motility factor receptor (AMFR, also gp78), a cancer-associated receptor and E3 ubiquitin ligase in endoplasmic reticulum associated degradation (ERAD) and ER-mitochondria interaction.
• Development of novel anti-cancer therapeutics based on the raft-dependent endocytosis of autocrine motility factor (AMF), the gp78/AMFR ligand.
• The role of plasma membrane domains and their effectors, including galectin-3 and caveolin-1, in receptor signaling and focal adhesion dynamics in metastatic cancer cells.
• Characterization of the proteome and transcriptome of tumor cell pseudopodia and the regulation of tumor cell migration and metastasis.

Christian Naus

Naus Lab Website

Gap Junctions in Neural Development and Disease
Gap junctions are collections of intercellular membrane channels that join adjacent cells in every organ of the body. They allow a variety of small molecules to pass freely from cell to cell, coupling the cells metabolically and allowing them to coordinate their responses to various signals. The importance of gap junctions has become evident with the identification of congenital diseases resulting from mutations in connexin genes, including X-linked Charcot-Marie-Tooth disease, congenital cataracts, deafness, heart defects and skin diseases. In addition, reduced gap junctional coupling between cells has been detected in several cancers, and increased coupling has implications for epilepsy and stroke. Most of these disease syndromes, to greater or lesser extent, are reproduced in transgenic mice lacking specific connexins.

The objective of my research program is to explore the role of gap junctions in neural development and disease, including consequences of connexin mutations on gap junction structure and function, and to explore the role of these intercellular channels in diagnosis of disease and development of novel therapeutic strategies.

My research in developmental neuroscience is aimed at exploring the function of gap junctional coupling in the developing brain, using pharmacological manipulation as well as genetically modified mice designed to express normal and mutant connexin genes with specific temporal and spatial expression patterns. The role of gap junctions in the etiology and possible therapy of neurological disorders is being examined in animal models and clinical tissues related to stroke, epilepsy and brain cancer. In the area of cell biology and cancer research, we have shown that tumour cells engineered to re-establish gap junctional communication show suppression in growth and tumorigenesis. A major focus of ongoing research is aimed at determining the mechanisms underlying this tumour-suppressive effect, using genomics approaches to identify some of the links between gap junctions and expression of growth control genes. We are also exploring the repertoire of endogenous molecules which pass through gap junction channels, some of which are likely to be involved in the control of cell growth and differentiation. Given the evidence that some tumour therapeutic agents readily pass through gap junctions to enhance tumour cell killing, this research is particularly relevant to the development of novel cancer therapies.

Tim O’Connor

O’Connor Lab Webpage

My lab is currently working on three main projects

(1) Intracellular signaling during neurite outgrowth and sprouting. The aim of this research is to identify the intracellular signaling mechanisms important for neuronal outgrowth and to determine their effect on the cytoskeletal network.  Recently we have shown that axon consolidation is an active process and that neurite sprouting is suppressed along the length of a neurite.  We are currently examining the regulation of this signaling mechanism and identifying approaches to inhibit the signaling and stimulate neurite sprouting.  In addition, we are also examining how the cytoskeleton changes in a neuron as it grows in its normal embryonic environment.  Using a model insect system of neuronal growth, we analyze the location and activity of key regulators of cytoskeleton function in order to assess how neurons grow and turn in response to embryonic guidance cues.  Using sophisticated imaging technologies we will provide some of the first observations of cytoskeletal dynamics of growing neurons in their embryonic environment.

(2) Identification of small molecules that stimulate neurite outgrowth and regeneration.  We have recently established a high throughput screen to identify novel compounds that will stimulate neuronal growth and regeneration on inhibitory substrates.  Our goal for this project is to test these molecules in animal models as potential ther apeutics to stimulate neuronal regeneration and sprouting in the injured spinal cord.  In the future we hope to similarly examine whether these molecules can provide therapeutic benefits to neurodegenerative disease models.

(3) Examination of the role of semaphorins during embryonic development.  The aim of this project is to determine the function of semaphorins in the developing nervous system.  Semaphorins are the largest class of guidance cue that is expressed in the developing nervous system and many of these molecules have been shown to repel or inhibit neurons as they grow.  We are particularly interested in the biochemical regulation of semaphorin function and the receptors and second messenger systems that are stimulated by semaphorins.  In addition, we are interested in examining the dynamic distribution of semaphorins, particularly with respect to the distribution of the functional regions of the semaphorin protein.  Presently we are working on Semaphorins 1, 2 and 5.

Nelly Pante

Pante Lab Webpage

My laboratory studies one of the fundamental molecular trafficking pathways within the cell: bidirectional transport of macromolecules between the nucleus and the cytoplasm. To investigate this problem we use cellular and molecular techniques in combination with fluorescence and electron microscopy. We also explore possible practical applications by incorporating viral research into our studies. We study how viruses deliver their genome to the cell nucleus. These studies on nuclear import of viral genomes are of particular importance because they may lead to the development of treatments and drugs that block nuclear uptake of viruses and thereby viral replication and propagation of infections. The viruses presently under investigation in our lab include Influenza virus, Hepatitis B virus and parvoviruses.
Molecular trafficking between the nucleus and the cytoplasm occurs through specialized multi-protein channels called nuclear pore complexes (NPCs). As the NPC is the major player in nucleocytoplasmic transport, we are also molecularly and structurally characterizing the NPC.

Hakima Moukhles

Moukhles Lab Webpage

Researching the role of dystroglycan, a protein associated with several forms of muscular dystrophy, in the central nervous system. Molecular mechanisms underlying the dystroglycan-mediated targeting and polarization of proteins in glial cells.

Doug Allan

Allan Lab Webpage

Neuronal specification during nervous system development and maturation in Drosophila
Complex nervous system function depends upon the generation of many different subtypes of neurons and the lifelong modulation of their function by intercellular communication. The identity and function of a particular neuronal subtype is a product of the unique repertoire of ‘terminal differentiation’ genes that it expresses (eg. guidance molecules, ion channels, receptors, neurotransmitter biosynthetic enzymes, neuropeptides etc).

These genes are turned on after the neuron is born, but how neurons turn on the right set of genes is still poorly understood. Two regulatory inputs have been shown to play a role in regulating the expression of such ‘terminal differentiation’ genes; 1) the unique code of transcription factors expressed within the neuron, and 2) factors/signals that are secreted from the target cell that the neuron innervates. Our studies in Drosophila have demonstrated that these two inputs may actually functionally intersect to determine the mature gene expression repertoire of neurons.

Our research aims to investigate the mechanisms by which neurons selectively express the genes that define their unique identities and functions, exploring the roles of combinations of transcription factors and extrinsic signals. The genes and mechanisms that govern cell specification are highly conserved from invertebrates to humans. Therefore, we can learn much about the fundamental principles and molecular mechanisms relevant to vertebrate neuronal differentiation using the simpler nervous system and genetic amenability of Drosophila.

Disruption of transcription factors has been linked to congenital neurological disorders, and disruption of intercellular communication and trafficking of target-derived signals has been implicated in neurodegenerative disorders. Our studies will provide a mechanistic understanding of how these factors control gene expression pertinent to neuronal function, advancing our understanding of the aetiology of neurological disorders.